Ziritaxestat Drug-Drug Interaction with Oral Contraceptives: Role of SULT1E1 Inhibition.

In vitro signals indicate that ziritaxestat is a weak cytochrome P450 (CYP) 3A4 inhibitor and inducer. Therefore, potential drug-drug interactions (DDIs) with oral contraceptives were examined at a time when ziritaxestat was under development for treatment of fibrotic diseases. This open-label, crossover (fixed sequence) DDI study enrolled healthy, nonpregnant women aged 18-65 years (n = 15) who were using highly effective contraception, such as a nonhormonal intrauterine device, bilateral tubal occlusion, or sexual abstinence. A single dose of oral contraceptive (0.03 mg ethinyl estradiol (EE) and 3 mg drospirenone (DRSP)) was administered on days 1, 8, and 18, and ziritaxestat 600 mg once daily was administered from days 8 to 23. Co-administration resulted in a 2.8-fold and 2.4-fold increase in EE maximum plasma concentration (Cmax ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC0-inf ), respectively (day 18 vs. day 1). DRSP Cmax and AUC0-inf increased by 1.1-fold and 1.2-fold, respectively. DRSP is a CYP3A4 substrate, meaning increased EE exposure with ziritaxestat was not due to CYP3A4 inhibition. Ziritaxestat inhibition of EE glucuronidation and sulfation was quantified by liquid chromatography with tandem mass spectrometry in day 1 and day 18 plasma samples after EE conjugate hydrolysis. The ratio of EE AUC from time of administration up to the time of the last quantifiable concentration (AUClast ) with/without hydrolysis by arylsulfatase was substantially lower on day 18 vs. day 1, suggesting ziritaxestat is a potent inhibitor of sulfation; EE glucuronidation was largely unaffected by ziritaxestat. In vitro assessment confirmed ziritaxestat is a potent inhibitor of sulfotransferase family 1E member 1 (half-maximal inhibitory concentration < 0.8 µM). These findings highlight the importance of assessing enzymes other than CYP3A4 when investigating potential DDIs with oral contraceptives.

Discovery of 9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one (GLPG1205), a Unique GPR84 Negative Allosteric Modulator Undergoing Evaluation in a Phase II Clinical Trial.

GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of GPR84 (PBI-4050) that displays relatively low potency and selectivity, a clear need exists for an improved modulator. Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led to the identification of potent and selective GPR84 inhibitor GLPG1205 (36). Compared with the initial hit, 36 showed improved potency in a guanosine 5'-O-[γ-thio]triphosphate assay, exhibited metabolic stability, and lacked activity against phosphodiesterase-4. This novel pharmacological tool allowed investigation of the therapeutic potential of GPR84 inhibition. At once-daily doses of 3 and 10 mg/kg, GLPG1205 reduced disease activity index score and neutrophil infiltration in a mouse dextran sodium sulfate-induced chronic inflammatory bowel disease model, with efficacy similar to positive-control compound sulfasalazine. The drug discovery steps leading to GLPG1205 identification, currently under phase II clinical investigation, are described herein.

Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors.

Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.

Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis.

Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid. Compound 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients.